Venous thromboembolism (VTE) is increased in cancer patients and is commonly referred to as cancer- associated thrombosis (CAT). Rates of VTE vary among different cancer types with pancreatic cancer having one of the highest rates of CAT (12-42%). This suggests that there are cancer type-specific mechanisms of VTE. We and others have used mouse models to investigate mechanisms of CAT in different types of cancer. Our previous studies have shown that tumor-derived tissue factor (TF) increases thrombus size in mice bearing human pancreatic tumors in a new model of CAT. We will build on this observation by determining the role of the intrinsic coagulation pathway, neutrophils/neutrophil extracellular traps (NETs) and tumor-derived and host-derived plasminogen activator inhibitor type-1 (PAI-1) in venous thrombosis in tumor-bearing mice. We have found that mice bearing human and murine pancreatic tumors have increased levels of circulating FIXa-antithrombin (AT) complexes (indicating activation of the intrinsic coagulation cascade), neutrophils, plasma citrullinated histone H3 (H3Cit) (indicating increased NET formation), and increased levels of PAI-1 (indicating a hypofibrinolytic state). In this proposal. we will use xenograft and allograft mouse models as well as multiple human and murine pancreatic cancer cell lines and patients derived xenografts. We will use genetic and pharmacologic approaches to comprehensively determine the roles of the intrinsic coagulation pathway, neutrophils, NETs and PAI-1 in pancreatic CAT. Targeting the intrinsic pathway, neutrophils/NETs and PAI-1 may reduce VTE in pancreatic cancer patients with less risk of bleeding.